Xanthine Oxidoreductase Inhibitors

Xanthine oxidase inhibitors are primarily used in the clinical prevention and treatment of gout associated with hyperuricemia. The archetypal xanthine oxidase inhibitor, Allopurinol has been shown to have other beneficial effects such as a reduction in vascular reactive oxygen species and mechano-energetic uncoupling. This chapter discusses these properties and their relevance to human pathophysiology with a focus on Allopurinol as well as newer xanthine oxidase inhibitors such as Febuxostat and Topiroxostat. Xanthine oxidase (XO) and xanthine dehydrogenase (XDH) are collectively referred to as xanthine oxidoreductase (XOR). XDH is initially synthesised as a 150-kDa protein from which XO is derived, e.g. under conditions of ischemia/hypoxia either reversibly by conformational changes (calcium or SH oxidation) or irreversibly by proteolysis, the latter leading to formation of a 130-kDa form of XO. Both, XO and XDH, catalyse the conversion of hypoxanthine via xanthine to uric acid, the former by using oxygen forming superoxide and hydrogen peroxide and the latter NAD⁺. However, XDH is in principle also able to generate ROS.